1, 2, 3, 4, 4alpha, 9, 10, 10alpha-octahydro-7-isopropyl-4alpha-methyl-1, 9-dioxophenanthrenes



1,2,3,4,4a,9,10,10a-OCTAHYDRO-7-ISOPROPYL-4a- METHYL-1,9-DIOXOPHENANTHRENES Robert P. Jacobson, Shrewsbury, Mass., assignor, by mesne assignments, to G. D. Searle & Co., Skokie, 11]., a corporation of Delaware No Drawing. Application October 21, 1953,

' Serial No. 387,521

1 Claim. (Cl. 260-586) The present invention relates to alkylated octahydrophenanthrene ketones and processes for the preparation thereof. In particular, it relates to 1,2,3,4,4a,9,l0,laoctahydro 7 isopropyl 4a methyl 1,9 dioxophenanthrenes, having the formula which may be obtained by oxidation of the corresponding 1,2,3,4,4a,9,10,10a octahydro 7 isopropyl 4amethyl-l-oxophenanthrene, of the formula As distinct from this I have found, surprisingly, that dehydroabietinol, upon treatment with phosphorus pentoxide, dehydrates and rearranges to a hydrocarbon mixture which manifests essentially the same physical properties displayed by Brossis corresponding intermediate, but which, upon ozonolysis and isolation according to the techniques hereinafter detailed, is converted to a 1,2,3,4,4a,9,10,l0a octahydro 7 isopropyl 44amethyl-l-oxo-phenanthrene showing [a]D +153". The two substances (Brossis monoketone and the one herein disclosed) appear to be stereoisomers.

In accordance with the present invention, either of the foregoing monoketones may be converted to the corresponding diketone by mild chromic acid oxidation, or the equivalent.

Thus, it will be recognized that the subject compounds can and do exist in various stereochemical configurations: to wit, rings A and B may alternatively be cis or trans, one to the other; and each of these forms, in turn, occurs in either of two enantiomorphic (and optically active) modifications, or as a racemic combination of these modifications.

The compounds to which this invention relates are useful in medicine as hormonal agents. More particularly,

' the instant compounds are of value in the treatment of various non-androgenic dysfunctions associated with adrenocorticoid imbalance. Thus, for example, being possessed of a potent myotrophic activity uncomplicated by the capacity for testoid stimulation which characterizes and delimits the anabolic utility of testosterone and other naturally occurring substances known to increase muscle strength and mass, the compounds of this invention are uniquely adapted to use in the care of premature infants,

1 the management of convalescence from acute illness and surgical procedures, and for long-term administration to patients with chronic debilitating disease.

The subject compounds are soluble in alcohol, as also in propylene glycol. They may be administered in solidform as tablets or capsules; dissolved or suspended in aqueous alcohols, they may be given parenterally.

The following preparations will illustrate in detail certain of the compounds which constitute the present invention and methods which have been devised for the manufacture thereof. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practiced without departing from the purpose and intent of. this disclosure.

. isopropyl-4a-methylphenanthrene.

In the preparations hereinafter detailed, temperatures are given in degrees centigrade C.) and relative amounts of materials in parts by weight, except as otherwise noted.

1 ethylidene 1,2,3,4,4a,9,10,10a octahydro 7- isopropyl 4a methylphenanthrene.-Methyl dehydroabietate (which may be obtained, for example, by cat- Ialytic dehydrogenation of abietic acid methyl ester) is converted to l,2,3,4,4a,9,10,l0a-octahydro-7-isopropyl- ],4adimethylphenanthrene-l-methanol (dehydroabietinol) by reduction of 50 parts thereof with 5 parts of lithium aluminum hydride in 230 parts of anhydrous ether. Work-up of the reaction mixture proceeds through dropwise addition of sufiicient ethyl acetate to react with excess hydride; followed by cautious introduction of water until hydrogen evolution ceases; and, finally, acidification of the cooled suspension obtained at this point with dilute hydrochloric acid. The ether layer is separated and washed with water, dilute aqueous sodium bicarbonate, and saturated aqueous sodium chloride, in that order. Solvent is stripped and the residue then distilled in vacuo. The 1,2,3,4,4a,9,l0,10a octahydro 7 -isopropyl 1,43.- d-imethylphenanthrene-lmethanol (B. P. 16l-163 C. at 0.2 mm. pressure) thus obtained is taken up in parts of anhydrous benzene and added to a stirred, boiling suspension of 50 parts of phosphorus pentoxide in 530 parts of commercial n-hexane which has been preliminarily treated by repeated boiling with (fresh) phosphorus pentoxide and subsequent distillation to the point where essentially no color develops in the boiling hexane-phosphorus pentoxide suspension. When the addition of carbinol is complete, the reaction mixture iscooled, and spent dehydrating agent is allowed to settle out. The supernatant hexane solution is decanted therefrom and the residue then washed superficially with (fresh) nhexane, these washings being combined with the decanted material. The hexane solution is now allowed to stand with intermittent agitation in contact with an aqueous slurry of sodium. bicarbonate until free of acid, after which it is separated, shaken with anhydrous sodium bicarbonate, filtered, and stripped of solvent under reduced pressure, in that order. Vacuum distillation of the oily residue affords a hydrocarbon mixture, one constituent of which is a l-ethylidene-1,2,3,4,4a,9,10,10a-octahydro-7- The mixture thus obtained shows B. P. 1l9-123 C. at 0.1 mm. pressure,

Patented Feb. 12, 1957.

[u] +202. The ethylidene compound thus obtained has the formula CH5 I OH(CH|)2 H CH 1,2,3,4,4a,9,10,10a -'octahydro'- 7-is0propyl-4a-methyll-oxophenanthrene semicarbazne.A solution of approximately 45 parts of a l-ethylidene-1,2,3,4,4a,9,10, 10a octahydro-7-isopropyl-4a-methylphenanthrene prepared as detailed above, in 415 parts of methyl acetate, is treated at 75 C. for approximately 6 hours with oxygen containing approximately 4% ozone. The desired ozonide thus formed has the formula The reaction mixture is steam distilled to remove solvent and decompose the ozonide. The product is extracted into ether; and the extract, after being washed with dilute aqueous sodium bicarbonate and then dried over anhydrous sodium sulfate, is stripped of solvent. The nearly colorless oil thus obtained is refluxed for 2 hours with methanolic semicarbazide prepared as follows: 65 parts of semicarbazide hydrochloride is triturated with 30 parts of anhydrous sodium carbonate in the presence of methyl alcohol, until carbon dioxide evolution ceases; the material is filtered; 6.5 parts of glacial acetic acid is added to the filtrate; and, finally, the volume of this filtrate is brought to approximately 100 times that of the added acid, with methyl alcohol. Precipitation usually occurs during the reflux period. The cooled reaction mixture is poured into approximately 3 volumes of well-stirred cold water, whereupon the precipitated solid is collected, washed with water, and dried in air. Repeated extraction of this material with small volumes of methyl alcohol leaves the desired semicarbazone as a sparingly soluble residue which, recrystallized from a mixture of methyl alcohol and chloroform, shows M. P. approximately 242 C. (with decomposition), and [a] +289. The l,2,3,4,4a,9,l0,10aoctahydro 7 isopropyl 4a methyl-l-oxophenanthrene semicarbazone thus prepared has the formula CH(CH lNHCONH: 1,2,3,4,4a,9,10,10rr-octahydro-7-isopropyl-4a-methyl-1 oxophenanthrene.-From the semicarbazone prepared as hercinabove detailed, the corresponding ketone is obtained by refluxing a suspension of 14 parts of the semicarbazone for 20 minutes in a mixture of 390 parts of methyl alcohol and 210 parts of water containing 14 parts of approximately 20% aqueous hydrochloric acid. Solution occurs in process. The reactants are poured into cold water, precipitating a viscous oil which is taken up in n-pentane, the resultant solution being filtered to remove a small amount of insoluble matter, then washed with water and finally dried over anhydrous sodium sulfate. Solvent is stripped in vacuo, following which the residue is distilled to give a colorless product, B. P. 120123 C. at 0.05 mm. pressure, [oz] +153. The material thus obtained is a 1,2,3,4,4a,9,10,10a-0ctahydro- 7-isopropyl-4a-methyl-l-oxophenanthrene of the formula Q ll Refiuxing of this ketone with methanolic hydroxylamine affords the oxime which, crystallized from methyl alcohol, shows M. P. 193199 C., [u] +292.

1,2,3,4,4a,9,10,10a octahydro 7-ispropyl 4a-methyl- 1,9-di0xophenanthrene.A solution of 5 parts of a 1,2,3, 4,4a,9,10,10a-octahydro 7-isopropy1-4a-methyl-l-oxophenanthrene in approximately 75 parts of acetic acid is cooled and mixed with 18 parts of a chromic acid solution consisting of 1 part of chromic anhydride and 4 parts aqueous acetic acid, and these reagents are maintained at about 35 C. for 2 /2 hours. An additional 15 parts of chromic acid solution is then mixed in and the reactants allowed to stand at the 35 temperature for 5 hours longer. Water is then added, following which the resinous product is extracted into ether. The ether extract is washed with water and dilute aqueous sodium bicarbonate solution, in that order; then dried over sodium sulfate; and, finally, stripped of solvent by distillation. The residue is induced to crystallize by treatment with n-pentane, and the solid thus obtained is recrystallized successively from a mixture of ether and n-hexane, and from aqueous methanol. The product, a l,2,3,4,4a,9,10,l0a octahydro -7 isopropyl 4a methyl-1,9-dioxophenanthrene, shows M, P. 1l7l18 C., [a] +144. It has the formula OH(CH3)2 I claim:

A 1,2,3,4,4a,9,l0,10a octahydro 7 isopropyl 4a methyl-1,9-dioxophenanthrene, having the formula References Cited in the file of this patent Cook et a=l.: Jour. Chem. Soc., 1944, pgs. 286-293.

Brossi et al.: Helv. Chim. Acta., 33, 1730 (1950).

Stork et al.: lour. Am. Chem. Soc. 73, pgs. 3544-6 (1951). 

